The progress in the treatment of many childhood cancers is a story of amazing successes. Survival for many childhood malignancies has improved logarithmically over the past three decades. However, despite these remarkable advances, many chemotherapeutic agents are associated with significant side effects-which can be debilitating and even life threatening in some cases. Advances in biomarker discovery, including genomics, pharmacogenomics, and proteomics, offer great hope to these patients in terms of improved therapeutic precision, safety, and efficacy. We propose to combine candidate pathway and informed candidate variant genomics with targeted proteomics, and circulating endothelial progenitor cell subsets (a cellular regulator of angiogenesis) in our focused multifactorial approach to optimized therapeutics in children. We hypothesize that combinations of carefully selected biomarkers are associated with phenotypic markers of toxicity and overall response to pediatric cancer chemotherapy. The objective of this center grant application is to identify the best combinations of biomarkers to predict response to anticancer chemotherapeutic agents in children. We propose three multidisciplinary and closely interlinked projects supported by our Administrative and Biostatistics and Modeling Cores. Project I will test the hypothesis that combinations of biomarkers are associated with carefully defined measures of vincristine neurotoxicity and pharmacokinetics in two pediatric patient populations. Project II wil use targeted proteomics and informed genomics to test whether a combination of biomarkers will be able to optimally predict the risk of hematopoietic stem cell transplant (HSCT) therapy-related sinusoidal obstruction syndrome in children in an observational trial. Project 111 will evaluate whether circulating cellular markers of angiogenesis and focused vascular endothelial growth factor pathway genetics are associated with 1) treatment efficacy in the solid tumor patients from project I and 2) risk of SOS in the HSCT patients from project II. The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. PUBLIC HEALTH RELEVANCE: We propose to improve the treatment of children with cancer by identifying the best combinations of biomarkers to predict response to anticancer chemotherapeutic agents. This will allow creation of new dosing algorithms to optimize the treatment of this pediatric population.